The effect of pharmacist‐led interventions on the management and outcomes in chronic kidney disease (CKD): A systematic review and meta‐analysis protocol

Abstract Background and Aims Chronic kidney disease (CKD) is a progressive condition that results in a decline in kidney function over time. There are several conditions that increase the likelihood of developing CKD, particularly diabetes and hypertension. CKD increases the risk of mortality and has a detrimental impact on quality of life (QoL). Strategies for managing CKD include controlling cardiovascular risk factors and treating complications of CKD. There is an ever‐increasing role of pharmacists in managing CKD, from the optimization of risk factors to patient education. However, currently, there is a lack of data on the effect pharmacist‐led interventions have on the clinical, economic, and humanistic outcomes. Methods This protocol, in adherence to PRISMA‐P (Preferred Reporting Items for Systematic review and Meta‐Analysis Protocols) standards, describes a prospective systematic review and meta‐analysis of randomized controlled trials, where any intervention led by a pharmacist in CKD is used. Comparison groups will consist of usual care or non‐pharmacist‐led interventions. Literature searches will be conducted in the following databases: MEDLINE, Scopus, and Web of Science. Data pertaining to clinical (e.g., mortality), economic (e.g., healthcare‐associated costs), and humanistic (e.g., QoL) outcomes will be extracted. Risk of bias will be assessed using the United States National Heart Lung and Blood Institute quality assessment tool for controlled intervention studies. A meta‐analysis will be conducted to synthesize appropriate comparable outcomes. Results The findings of this review will be published in a peer‐reviewed journal, where the results will be presented in lay language with appropriate infographics online and via social media. Conclusion The findings of this review can identify gaps in the literature concerning optimizing pharmacist‐led interventions in improving outcomes. In addition, this review will establish the importance of pharmacists in managing CKD patients, and whether this may result in their increased incorporation in multidisciplinary teams.


| INTRODUCTION
Chronic kidney disease (CKD) is a condition characterized by the gradual change in the function and structure of kidneys over time. 1 It is defined as a reduction in kidney function, with an estimated glomerular filtration rate (eGFR) of <60 ml/min per 1.73 m 2 and/or markers of kidney damage for at least 3 months. 2 Kidney replacement therapy (KRT), such as dialysis or kidney transplantation, is offered to patients whose kidney function has deteriorated and who have consequently developed kidney failure (i.e., an eGFR <15 ml/min per 1.73 m 2 ). 3 Whilst there are several aetiologies of CKD, including diabetes and hypertension, 4 the prevalence of CKD increases with age. 5 CKD has a prevalence of around 14% in those aged 30 years and over, increasing to 34% in people in over 70 years. 6 Kidney function steadily declines over time, with a mean annual rate of change in eGFR of approximately 1 ml/min per 1.73 m 2 . 7 The loss of function can be attributed to reductions in afferent arteriolar resistance, glomerular capillary plasma flow rate and kidney mass, alongside other haemodynamic and structural changes. 8 Multimorbidity is also becoming increasingly prevalent in older adults, 9 where chronic conditions like diabetes and hypertension often coexist and can further increase the risk of CKD. 10 CKD can have a significantly detrimental impact on quality of life (QoL) and can result in adverse health outcomes such as an increased risk of cardiovascular disease, 11 anaemia, and mineral and bone disorders. 12 Effective identification and management of the condition, which is primarily conducted in primary care, 13 is essential. Management of CKD patients is multifactorial, where the aims are to identify and control risk factors such as hypertension with the use of renin-angiotensin aldosterone system (RAAS) inhibitors, angiotensin-converting enzyme inhibitors or angiotensin receptor antagonists, lipid reduction with the use of statins and various glucose-lowering pharmacological agents for diabetes. 1 Risk factor optimization is part of a holistic approach towards CKD management, alongside lifestyle modifications, the treatment of comorbidities, complications and symptoms, and reduction in the progression of eGFR decline with the use of pharmacological therapies such as RAAS inhibitors and sodium-glucose cotransporter-2inhibitors. 1 Patients who reach an advanced stage of CKD require a multidisciplinary approach to manage their symptoms and improve their QoL, where dialysis or kidney transplantation can be offered as options for KRT. 1,14 Polypharmacy is prevalent in kidney transplant patients, where they often take immunosuppressants and medications to prevent graft rejection and to manage other comorbidities. 15 Where KRT is not appropriate, conservative care can be offered, which consists of symptom management, the provision of palliative care, and advancecare planning. 16 Pharmacists provide a valuable contribution in managing CKD patients and improving their clinical, economic, and humanistic outcomes, either individually or as part of a wider multidisciplinary team. A 2-year prospective cohort study by Leung et al. 17 that compared structured care provided by a pharmacist-diabetes specialist team to usual care resulted in a reduction in the incidence of end-stage kidney disease or death in patients with type 2 diabetic nephropathy. Pharmacists can primarily help in managing drug-related problems. A retrospective study by Daifi et al. 18 demonstrated that a clinical pharmacist who conducted medication reconciliation and medication reviews in haemodialysis patients identified over 1400 drug-related problems and saved approximately US$450,000.
Pharmacists may also provide routine care of risk factor control and selfmanagement education programmes. Pharmacists have also played a crucial role in managing CKD patients during the COVID-19 pandemic, from identifying and preventing potential or actual drug-drug interactions to making dose adjustments or optimizing doses of medication indicated for COVID-19, as per the patient's kidney function. 19 There is growing evidence that pharmacists can improve outcomes in patients with CKD and there remains a growing opportunity to improve their incorporation into CKD healthcare teams. 20 Nonetheless, data on how pharmacists are most effectively used in the management of CKD is limited, and optimizing interventions delivered by pharmacists may help improve the care of people living with CKD.
The purpose of this review is to identify pharmacist-led interventions in management of CKD, including dialysis and nondialysis patients, and the effect on clinical, economic, and humanistic outcomes, compared to usual care or appropriate comparison group (e.g., nonpharmacist intervention). Whilst several previous reviews have been undertaken exploring the effect of pharmacist interventions in CKD, they have included various types of research study designs and had a narrow search strategy, [21][22][23] where they had a limited number of search terms and did not have any for the key concept of "intervention." Moreover, two of these systematic reviews are out-of-date, 22,23 where research has been conducted since their publication as recently as 2021, with two randomized controlled trials (RCTs) that investigated the impact of pharmacist-led mobile health interventions in kidney transplant patients. 24,25 This contemporary review will have a broader search strategy encompassing a range of outcomes to provide a comprehensive overview of pharmacist interventions in CKD. Furthermore, it will include only RCTs, the highest level of evidence, 26 and a meta-analysis will aim to synthesize appropriate comparable outcomes.

| METHODS
The systematic review protocol is registered on the International Prospective Register of Systematic Reviews (PROSPERO) (Registration number: CRD42022304902). The protocol has been developed in adherence to PRISMA-P (Preferred Reporting Items for Systematic review and Meta-Analysis Protocols) standards 27 (see Supporting Information Material S1).

| Eligibility criteria
Inclusion and exclusion criteria can be found in Table 1.

| Information sources
Searches of existing and completed systematic reviews will be conducted on the Cochrane Library and PROSPERO databases, and we will screen their reference lists to identify any potential eligible studies. Literature searches will be conducted in the following databases: MEDLINE, Scopus, and Web of Science. A combination of free-text terms and medical subject heading (MESH) terms will be used to search MEDLINE, whereas only free-text searching will be used for Scopus and Web of Science. Database searches will be supplemented with internet searches (i.e., Google Scholar) and

| Selection process
Results from the searches will be combined in EndNote 20 (Clarivate Analytics), where duplicates will be removed before uploading retrieved references to the Covidence systematic review management system (www.covidence.org). 28 Two independent reviewers will screen initial title and abstracts for inclusion. Any uncertainties or disagreements that arise will be resolved with input from a third reviewer. Full texts will be obtained for references not excluded during title and abstract screening and will be independently screened by two reviewers.

| Data collection process
One reviewer will extract data and a second will check for accuracy.
A bespoke extraction form will be created to document extracted information from the studies. The form will be piloted and amended, if necessary, before full extraction.

| Data items
The extracted information will include the following: sociodemographic (e.g., age, sex and ethnicity) and clinical characteristics (eGFR, systolic blood pressure and diastolic blood pressure); a description of details of the intervention and control groups such as sample size, type of intervention and duration; primary and secondary outcomes; and key conclusions from the authors. In addition, information will be extracted on the resources available for pharmacists for provision of care and the processes they carry out.

| Outcomes and prioritization
Data will be extracted based on economic (e.g., cost of inappropriately prescribed medications and hospitalization-associated costs), humanistic outcomes (e.g., QoL and patient knowledge) and clinical (e.g., blood pressure and mortality) measures (see Table 2 for definition of clinical, economic, and humanistic outcomes).

| Risk of bias in individual studies
Two reviewers will independently assess the risk of bias using the United States National Heart Lung and Blood Institute (US NHLBI) quality assessment tool for controlled intervention studies. 30  is a disagreement between them, input from a third reviewer will be provided to reach a consensus. In addition, an Egger's test will be used to identify potential publication bias. 31

| Data synthesis
A narrative synthesis will be created from the included studies structured around the type of intervention, target population characteristics and outcome measures. Where appropriate (e.g., comparable outcomes across studies), Review Manager (RevMan Version 5.4.1) software (The Cochrane Collaboration) will be used to analyse data, where continuous data will be expressed as a mean or standardized mean difference with a 95% confidence interval and dichotomous outcomes will be presented as either relative risk or odds ratio. Data will not be pooled if heterogeneity is moderate (I 2 statistic greater than 40%). 32 Moreover, the level of significance will be set at <0.05. If heterogeneity is identified, potential causes will be explored (e.g., clinical and/or methodological diversity). We will explore heterogeneity via subgroup analysis, but if this cannot be explained, then a narrative approach will be taken, and a metaanalysis will not be performed. Studies with a moderate or high risk of bias will be removed from analyses to determine the extent to which synthesized results are sensitive to risk of bias.

| Analysis of subgroups or subsets
If possible, we will conduct subgroup analyses across the different disease staging, (e.g., nondialysis, dialysis, transplantation), the type of pharmacist-led interventions, the presence of comorbidities, if interventions delivered were by a multidisciplinary team including a pharmacist or were pharmacist-led, and by sociodemographic groupings (e.g., sex, ethnicity, age). Pharmacists are well placed with their clinical and therapeutic knowledge to provide pharmaceutical and nonpharmaceutical recommendations and interventions for CKD patients. The aim of this systematic review and meta-analysis is to explore the impact of pharmacist-led interventions in managing clinical, economic, and humanistic outcomes of CKD patients enrolled in RCTs. The findings of this review will be published in a peerreviewed journal, where the results will be presented in lay language with appropriate infographics online and via social media. Moreover, any potential gaps in the literature may be identified with regards to pharmacist interventions, where information from this review will be utilized to ascertain what aspects of interventions delivered by a pharmacist (e.g., patient education) were able to improve clinical, economic and/or humanistic outcomes. Consequently, trials can be devised to optimize and address them, alongside identifying alternative models of care that may help with redesigning services to manage people with CKD. In addition, this review will look to establish the importance of pharmacists in managing CKD patients compared to those receiving usual care, and whether this potentially will result in increased incorporation of pharmacists in multidisciplinary teams and/or more interventions delivered solely by the pharmacist which will optimize practice in the future.

| DISCUSSION
(ARC EM) and University of Leicester. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.

CONFLICTS OF INTEREST
The authors declare no conflicts of interest.

DATA AVAILABILITY STATEMENT
Data will be made available upon reasonable request. Further enquiries can be directed to the corresponding author. TJW have full access to all of the data in this study and takes complete responsibility for the integrity of the data and the accuracy of the data analysis.

ETHICS STATEMENT
An ethics statement is not applicable because this study is based exclusively on published literature.

TRANSPARENCY STATEMENT
The lead author Ashkon Ardavani affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.